The Pima Indians of Arizona have the highest prevalence and incidence rate of noninsulin dependent diabetes mellitus (NIDDM) of any population in the world. We have been studying a subset of this population that is at highest risk of developing the disease for the purposes of 1) to determine the metabolic characteristic(s) which is most predictive of the subsequent development of NIDDM among non-diabetics and 2) to document the sequence of metabolic events that occur at the transition from normal to impaired glucose tolerance and subsequently to marked fasting hyperglycemia and NIDDM. Indian volunteers are admitted to the clinical research ward for about ten days to undergo a variety of tests to assess body composition, oral and intravenous glucose tolerance, insulin secretory dynamics, energy metabolism, and insulin action. To date the results have shown that insulin resistance is a major and significant predictor of the subsequent development of NIDDM among non-diabetic subjects. The transition from normal to impaired glucose tolerance is associated with deterioration of insulin action in vivo and the insulin response to the development of this insulin resistance appears to be appropriate for the degree of glycemia that occurs with the impaired glucose tolerance. Transition from impaired glucose tolerance to marked fasting hyperglycemia is then associated with the deterioration in insulin secretory dynamics. Comparison with Caucasians has shown that Pima Indians are more insulin-resistant at a given degree of obesity. More notable, however, is that even when matched for insulin resistance or obesity, Pima Indians have greater insulin responses to glucose or a meal. The differences are particularly notable at earliest time points after a stimulus and this suggests that poor pancreatic function does not underlay diabetes in this population. In collaboration with other laboratories, the insulin gene and the insulin receptor gene have both been sequenced in Pima Indians and found to be normal.